Autism spectrum disorder (ASD) is characterized by a complex polygenic background, but with the unique feature of a subset of cases (~15%‐30%) presenting a rare large‐effect variant. However, clinical interpretation in these cases is often complicated by incomplete penetrance, variable expressivity and different neurodevelopmental trajectories. NRXN1 intragenic deletions represent the prototype of such ASD‐associated susceptibility variants. From chromosomal microarrays analysis of 104 ASD individuals, we identified an inherited NRXN1 deletion in a trio family. We carried out whole‐exome sequencing and deep sequencing of mitochondrial DNA (mtDNA) in this family, to evaluate the burden of rare variants which may contribute to the phenotypic outcome in NRXN1 deletion carriers. We identified an increased burden of exonic rare variants in the ASD child compared to the unaffected NRXN1 deletion‐transmitting mother, which remains significant if we restrict the analysis to potentially deleterious rare variants only (P = 6.07 × 10⁻⁵). We also detected significant interaction enrichment among genes with damaging variants in the proband, suggesting that additional rare variants in interacting genes collectively contribute to cross the liability threshold for ASD. Finally, the proband's mtDNA presented five low‐level heteroplasmic mtDNA variants that were absent in the mother, and two maternally inherited variants with increased heteroplasmic load. This study underlines the importance of a comprehensive assessment of the genomic background in carriers of large‐effect variants, as penetrance modulation by additional interacting rare variants to might represent a widespread mechanism in neurodevelopmental disorders.

中文翻译：

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NRXN1 微缺失携带者中罕见外显子变异的负担增加可能会提高自闭症谱系障碍的外显率

自闭症谱系障碍 (ASD) 的特点是复杂的多基因背景，但具有独特的特征，即部分病例 (~15%-30%) 呈现出罕见的大效应变异。然而，这些病例的临床解释往往因不完全外显率、可变表达能力和不同的神经发育轨迹而变得复杂。NRXN1基因内缺失代表了这种 ASD 相关易感性变异的原型。通过对 104 名 ASD 个体的染色体微阵列分析，我们在一个三重奏家族中发现了遗传的NRXN1缺失。我们对该家族中的线粒体 DNA (mtDNA) 进行了全外显子组测序和深度测序，以评估可能导致NRXN1表型结果的罕见变异的负担删除载体。与未受影响的NRXN1缺失传递母亲相比，我们发现 ASD 儿童中外显子罕见变异的负担增加，如果我们将分析仅限于潜在有害的罕见变异，这仍然显着（P  = 6.07 × 10 ^-5）。我们还检测到先证者中具有破坏性变异的基因之间显着的相互作用富集，这表明相互作用基因中的其他稀有变异共同有助于跨越 ASD 的责任阈值。最后，先证者的 mtDNA 呈现出母亲中不存在的五种低水平异质 mtDNA 变异，以及两种异质负荷增加的母系遗传变异。这项研究强调了对大效应变异携带者的基因组背景进行全面评估的重要性，因为通过额外的相互作用罕见变异进行外显率调节可能代表神经发育障碍的普遍机制。